Design

Setting

34 centers in North America and Europe.

Patients

428 patients who were 19 to 78 years of age (median age range for groups 51 to 56
y, 78% women); had a diagnosis of RA according to the 1987 American College of Rheumatology
(ACR) criteria with evidence of active disease after treatment with methotrexate for
≥ 3 months; had received stable doses of methotrexate, ≥ 12.5 mg/wk, and
folic acid for ≥ 4 weeks before screening; and had hemoglobin levels ≥ 5.3
mmol/L, white blood cell counts ≥ 3.5 × 109/L, a neutrophil count of 1.5 × 106/L, platelet counts ≥ 100 × 109/L, and normal liver and renal function. Patients who received oral corticosteroids
were included if their dose had been stable for ≥ 4 weeks. Exclusion criteria
included current inflammatory conditions, use of drugs other than methotrexate for
RA, known allergy to murine proteins, previous or recent infections, or serious medical
conditions. 81% of patients completed the study.

Main outcome measure

Response rate at week 30 (defined as 20% improvement from baseline according to ACR
criteria).

Main results

More patients in the infliximab groups than in the placebo group had a 20% improvement
(P < 0.001) (Table). Serious adverse effects did not differ among groups. Infection
occurred more frequently in the 10-mg infliximab groups (64% in 8-week group, 73%
in 4-week group) than in the placebo group (40%, P ≤ 0.001).

Conclusion

In patients who have rheumatoid arthritis and did not respond to methotrexate, infliximab
was effective for relieving signs and symptoms.

†Abbreviations defined in Glossary; RBI, NNT, and CI calculated from data in article.

Commentary

The study by Maini and colleagues shows that antitumor necrosis factor α (TNF-α) blockade
(infliximab) acts synergistically with methotrexate to suppress the acute-phase response
and to reduce rheumatoid synovitis. However, 50% improvement was achieved in only
26% to 31% of patients in the treatment groups in a 30-week trial. Thus, it is important
to identify the patients most likely to benefit from this expensive treatment. The
disease duration ranged from 7.2 to 9.0 years, and 18% to 29% of patients had already
had joint surgery. Earlier treatment with TNF-α blockade might prove more effective.

The long-term safety of TNF-α blockade is of concern. The incidence of infection was
higher in the treatment groups, and the authors reported that such infections may
be serious for some patients in the longer term. The relative merits of new antirheumatic
agents must also be considered. Etanercept has proved to be as effective and well
tolerated as infliximab in suppressing both the acute-phase response and synovitis
in short-term trials (1). It is given subcutaneously but is used more frequently than infliximab. Unlike
infliximab, etanercept does not induce antibodies to the drug. However, it is also
expensive. Leflunomide substantially suppresses both the acute-phase response and
synovitis. Diarrhea is the main side effect (2). Leflunomide is given orally and is far less expensive than infliximab or etanercept.
Furthermore, it improves patients’ health-related quality-of-life scores (3).

These new agents offer a realistic prospect of more effective treatment for RA. Their
efficacy, relative merits, and indications for use can only be established in long-term
studies that address the stage at which they should be introduced, their ability to
suppress joint erosion, safety issues, and cost-effectiveness. Currently, leflunomide
is a simple alternative to methotrexate, whereas infliximab or etanercept should be
reserved for patients in whom other treatments have failed.